Abstract
The RET proto-oncogene is the major gene involved in the pathogenesis of Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia along variable lengths of the gut. Here we present a survey of the different molecular mechanisms through which RET mutations lead to the disease development. Among these, loss of function, gain of function, apoptosis, aberrant splicing and decreased gene expression are exemplified and considered with respect to their pathogenetic impact. In particular, RET transcription regulation represents a new insight into the outline of HSCR susceptibility, and having reached important progress in the last few years, deserves to be reviewed. Notably, gene expression impairment seems to be at the basis of the association of HSCR disease with several RET polymorphisms, allowing us to define a predisposing haplotype spanning from the promoter to exon 2. Putative functional variants, in the promoter and in intron 1, and proposed as low penetrant predisposing alleles, are presented and discussed. Finally, based on the RET mutation effects thus summarized, we attempt to derive conclusions which may be useful for HSCR risk prediction and genetic counselling.
| Original language | English |
|---|---|
| Pages (from-to) | 11-19 |
| Number of pages | 9 |
| Journal | Annals of Medicine |
| Volume | 38 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Mar 2006 |
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Keywords
- Apoptosis
- Complex inheritance
- Disease predisposition
- Genetic counselling
- Hirschsprung disease
- Loss-of-function
- Molecular pathogenesis
- RET proto-oncogene
- RNA splicing
- Transcription regulation
ASJC Scopus subject areas
- Medicine(all)
Cite this
Molecular mechanisms of RET-induced Hirschsprung pathogenesis. / Lantieri, Francesca; Griseri, Paola; Ceccherini, Isabella.
In: Annals of Medicine, Vol. 38, No. 1, 03.2006, p. 11-19.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Molecular mechanisms of RET-induced Hirschsprung pathogenesis
AU - Lantieri, Francesca
AU - Griseri, Paola
AU - Ceccherini, Isabella
PY - 2006/3
Y1 - 2006/3
N2 - The RET proto-oncogene is the major gene involved in the pathogenesis of Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia along variable lengths of the gut. Here we present a survey of the different molecular mechanisms through which RET mutations lead to the disease development. Among these, loss of function, gain of function, apoptosis, aberrant splicing and decreased gene expression are exemplified and considered with respect to their pathogenetic impact. In particular, RET transcription regulation represents a new insight into the outline of HSCR susceptibility, and having reached important progress in the last few years, deserves to be reviewed. Notably, gene expression impairment seems to be at the basis of the association of HSCR disease with several RET polymorphisms, allowing us to define a predisposing haplotype spanning from the promoter to exon 2. Putative functional variants, in the promoter and in intron 1, and proposed as low penetrant predisposing alleles, are presented and discussed. Finally, based on the RET mutation effects thus summarized, we attempt to derive conclusions which may be useful for HSCR risk prediction and genetic counselling.
AB - The RET proto-oncogene is the major gene involved in the pathogenesis of Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia along variable lengths of the gut. Here we present a survey of the different molecular mechanisms through which RET mutations lead to the disease development. Among these, loss of function, gain of function, apoptosis, aberrant splicing and decreased gene expression are exemplified and considered with respect to their pathogenetic impact. In particular, RET transcription regulation represents a new insight into the outline of HSCR susceptibility, and having reached important progress in the last few years, deserves to be reviewed. Notably, gene expression impairment seems to be at the basis of the association of HSCR disease with several RET polymorphisms, allowing us to define a predisposing haplotype spanning from the promoter to exon 2. Putative functional variants, in the promoter and in intron 1, and proposed as low penetrant predisposing alleles, are presented and discussed. Finally, based on the RET mutation effects thus summarized, we attempt to derive conclusions which may be useful for HSCR risk prediction and genetic counselling.
KW - Apoptosis
KW - Complex inheritance
KW - Disease predisposition
KW - Genetic counselling
KW - Hirschsprung disease
KW - Loss-of-function
KW - Molecular pathogenesis
KW - RET proto-oncogene
KW - RNA splicing
KW - Transcription regulation
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UR - http://www.scopus.com/inward/citedby.url?scp=31744442077&partnerID=8YFLogxK
U2 - 10.1080/07853890500442758
DO - 10.1080/07853890500442758
M3 - Article
C2 - 16448984
AN - SCOPUS:31744442077
VL - 38
SP - 11
EP - 19
JO - Annals of Medicine
JF - Annals of Medicine
SN - 0785-3890
IS - 1
ER -